Hemoglobin-digesting parasites, including the malaria parasites Plasmodium falciparum and Plasmodium vivax generate significant concentrations of free ferrous iron heme, which is formed as a result of hemoglobin catabolism by the parasite. These reactive forms of iron present an opportunity for iron(II)-targeted drug delivery, since free forms of ferrous iron are exceedingly rare in healthy tissue and cells. We have developed and validated in animals an iron(II)-targeted drug delivery technology for delivery of therapeutics to the malaria parasites, or more generally, to any biological compartment containing unbound ferrous iron. Drug delivery strategies have scarcely been investigated in anti-parasitic therapy but these approaches have the potential to target parasites selectively, protecting the patient from exposure to active drug species and possibly allowing the safe use of a broader range of therapeutics. Our delivery systems are comprised of a 1,2,4-trioxolane ring system as an iron(II)-sensing 'trigger' moiety and a 'traceless' linker to which the partner drug is attached an ultimately released via a -elimination reaction. The chemical design is such that drugs from a wide swath of chemical and therapeutic target space can in principle be delivered using the approach. In preliminary work, we synthesized prototypical delivery systems and demonstrated the iron(II)-dependent and parasite-selective delivery of a cysteine inhibitor to Plasmodium berghei parasites in infected mice. The goals of the proposed research are to evaluate in animals a new generation of more drug-like delivery systems, and to identify partner drug species that are optimally suited for this new approach to antimalarial therapy.